How to interpret a VDR test

Based on the current evidence (see previous posts) I would interpret the VDR tests as follows (remember FFbb is the "ideal" genotype for GcMAF):

1. Yasko / Holistic Health

I would take the Yasko Fok results as given so:
-/- corresponds to FF
+/- corresponds to Ff
+/+ corresponds to ff

If you have a Taq result only, with 95% confidence (since Taq and Bsm "track" each other 95% of the time):
-/- corresponds to BB
+/- corresponds to Bb
+/+ corresponds to bb

If you have a separate Bsm result (old style test) then the above still applies, but without the 5% uncertainty.

2. Red labs

If you have a red labs test I would take the Fok results as follows:
"High responder" corresponds to ff
"Moderate responder" corresponds to Ff
"Low responder" corresponds to FF

I would take the Bsm result as:
"High responder" corresponds to bb
"Moderate responder" corresponds to Bb
"Low responder" corresponds to BB


Disclaimer: All of the above is my current best-guess based on the evidence I have available right now, and should not be taken as definitive. Also we don't know how important VDR genetics are to GcMAF treatment, as compared to other factors, e.g. length of illness, age, number/type of co-infections, endocrine health, current level of functioning etc.

VDR Genetics Part 3: Fok

If you recall from the previous post, we were looking at the VDR SNPs Bsm and Fok that are used to predict the potential response to treatment with GcMAF. Two labs (Yasko's lab & Red labs) test for these SNPs, and they are both producing directly opposite results.

The previous post looked at the evidence to show which lab was producing the correct answer for the Bsm SNP. This post will look at the Fok SNP for the two labs.

The Fok SNP is a lot easier to deal with than Bsm.

For example this table here shows the distribution of Fok genotypes across various populations:

http://www.bioline.org.br/showimage?hg/photo/hg03011t2.jpg

As can be seen the wildtype -/- genotype, FF, is much more common across all populations than the double mutation +/+, ff, genotype (between 2 and 10 times more common).

Also this study mentioned in a previous post which looked at white non-Hispanic Americans shows that FF is over 3 times more common than ff:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938035/table/T3/

In particular the frequency of FF is 40.9% and that of ff is 12.0% for healthy controls (N=805).

According to Yasko's testing the FF genotype has a frequency of 38.3% and the ff genotype a frequency of 12.8% amongst ME/CFS patients (N=47). As can be seen these are very similar to the VDR Fok frequencies published in the literature.

Again, the above argument suffers from a potential flaw. It is possible that the most common allele in ME/CFS differs from controls for the VDR Fok SNP, and that therefore Yasko's reporting for this SNP is wrong.

To counter this argument we look at call letters.

Yasko's call letters for the Fok SNP are +T/-C as can be verified from the example test here:

http://i1186.photobucket.com/albums/z380/John_Garcia/genetics.jpg


The call letters for Fok reported in the literature are also +T/-C:

http://jid.oxfordjournals.org/content/197/3/405/F4.large.jpg

We can therefore conclude that as far as the Fok SNP is concerned Yasko's results seem to be accurate, and Red labs results seem to be in doubt.

Conclusion: Given all available evidence, right now I would trust Yasko's results for the Fok SNP, and redlabs results for the Bsm SNP.

VDR Genetics Part 2: Bsm

Mindy Kitei has recently posted 2 blogs regarding the discrepancy in testing for the Bsm SNP:

CFS Central: Gene Pool

CFS Central: Genes Redux

In particular she tentatively concludes (based on a statistical analysis) that Yasko's Bsm reporting of what is Wild-type (-/- or bb) and what is a mutation (+/+ or BB) are opposite to the standard reporting.

I can add to Mindy's evidence, by using two arguments.

1. Population Frequencies
According to Yasko's results BB is more common than bb in the ME/CFS population.

All the literature I have searched states bb is way more common than BB, in both the general population and disease groups.

For example in these 2 studies on the Japanese, the BB genotype is exceptionally rare (less than 1%):

1. http://ajrccm.atsjournals.org/cgi/content/full/160/4/1107
2. http://jcem.endojournals.org/cgi/content/full/88/7/3137/T1

It is possible that the Japanese may have unusual genetics though.

The following study, however, is on non-Hispanic white Americans:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938035/

In particular table 3 from that paper shows that BB has a frequency of 17.7% and bb 31.5%. This contrasts with Yasko's figures of 34% for BB and 14.9% for bb.

So in other words what Yasko calls -/- for Bsm is most likely in fact +/+ (and vice versa).

There is a potential flaw in the above frequency analysis in that it could be that the frequencies for the Bsm SNP are just so different in the ME/CFS population that the most common allele is reversed.

Indeed from the gene chart Mindy Kitei & W. L. Karns compiled, of 6 SNPs which differ with statistical significance from controls, 2 of them (COMT, MTRR) are so different that the most common allele in ME/CFS is reversed.

2. Call letters

As second more robust argument can be made by looking at the call letters for the + and - alleles for Bsm. On Yasko's test Bsm is +G/-A. In other words G represents a mutation or +, and A represents a wild-type allele or -.

However if we look at this HIV study here:

http://jid.oxfordjournals.org/content/197/3/405/F4.large.jpg

we can see from the figures for both HIV and controls that G is the common/wild-type allele and A is the mutation (GG is roughly twice as common as AA).

Conclusion

Yasko's lab seem to be reporting Bsm the opposite to the standard nomenclature. 
Red labs however seem to be reporting Bsm correctly.

Therefore the ideal Bsm genotype for GcMAF, namely bb, corresponds to +/+ on a Yasko test for Bsm/Taq.

That just leaves the Fok SNP which will be dealt with in Part 3.

VDR Genetics Part 1: Introduction

[Update Oct 2011: Since first writing this back in January new information has come to light. I no longer believe that VDR genetics have any significant effect on GcMAF-response (this is professor Yamamoto's position too). I believe other factors are far more significant - e.g. which coinfections a person has, whether their immune system is geared towards producing excessive inflammation, and the health of the HPA-axis]

There has been much confusion recently over the VDR (Vitamin D Receptor) tests which ME/CFS patients have taken in order to find out their potential response to GcMAF.

A paper by Ruggiero, Pacini & Yamamoto states that

"In fact, subjects harbouring homozygous “bb/FF” genotypes showed the highest response ... Heterozygous subjects (“Bb/Ff”) showed a smaller, but still significant, response, whereas “BB/ff” homozygous did not respond."

First a word on notation. An SNP (single-nucleotide polymorphism, pronounced "snip") is a part of a gene, e.g. the VDR gene, that varies from person to person. Fok1 and Bsm1 (hence shortened to Fok and Bsm respectively) are two SNPs of the VDR gene - i.e. two nucleotides that vary from person to person.

Normally in genetics, a capital letter denotes the "wild-type", dominant or non-mutated version of a SNP (e.g. "F" for the Fok SNP). The corresponding lower-case letter will then denote the mutated or recessive version of the SNP (e.g. "f" for Fok). However (as first pointed out to me by Joey Tuan), for Bsm the standard terminology is reversed. So bb refers to -/- (wild-type) and BB refers to +/+ (mutation).

[See Figure 2 from here for confirmation of the above: http://www.roche-applied-science.com/PROD_INF/BIOCHEMI/no3_05/pdf/p07.pdf]

Labs

The two main labs from which patients have tested are Amy Yasko's Holistic Health, and Red labs (who outsource testing to another unnamed lab).

Yasko's lab tests a range of genetics relating to methylation, Vitamin D, ACE etc. An example Yasko test can be seen here:

http://i1186.photobucket.com/albums/z380/John_Garcia/genetics.jpg

Red labs have a specific VDR genetics test where they test the two VDR SNPs Fok and Bsm.

Bsm = Taq (in most cases)

Yasko used to test the 3 VDR SNPs Fok, Bsm and Taq. However more recently they no longer test VDR Bsm, and instead only test VDR Taq. The reason for this is because they claim that VDR Bsm and Taq "track" each other for the vast majority of people, i.e. a mutation in one SNP corresponds to a mutation in another.

This claim is supported by the literature. I've been looking at a few VDR studies on population distributions of Taq & Bsm, and the numbers do seem to correlate (i.e. the numbers of tt would roughly equal BB, Tt would roughly equal Bb and TT would equal bb). The numbers alone don't tell us if the exact same people who have tt have BB etc. (we need joint distributions for that), but then I also found this study here:
http://www.springerlink.com/content/9hjra4g5wxd814tc/

which looks at 3 VDR snps: Apa, Bsm, and Taq. In particular they say:

The most common genotypes observed in our population were AaBbTt (37%), AABBtt (20%), aabbTT (15%), AabbTT (15%), and AABbTt (9%).

Ignore the Aa part since we are not interested in the Apa snp. But as you can see all of the above groups are people for whom Bsm and Taq are correlated (i.e. if BB then tt, if bb then TT, if Bb then Tt). Together that accounts for (37+20+15+15+9 =) 95% of the population. i.e. in that group of 120 people 95% had Bsm and Taq correlated.

Also from this paper here:

BsmI and TaqI genotypes were related in 89 of the 90 cases; hence, the same associations were found for both genotypes.

So it does seem that what Yasko is saying is true. Therefore people with a new style Yasko test can still deduce their Bsm status (by looking at Taq), albeit with slightly less than 100% certainty.

Why is this important?

Well we can directly compare the VDR genetics results given by the Yasko test with those given by Red labs.

Quite a few ME/CFS patients have tested using both labs and it appears that in every case so far Yasko's results for both Bsm and Fok are directly opposite to those of Red labs. For example if someone is +/+ for either Bsm or Fok by Yasko, they will show as -/- for that SNP by redlabs. Conversely if someone is -/- for either Bsm or Fok by Yasko, they will show as +/+ for that SNP by redlabs. Obviously heterozygous genotypes, +/- will show up as heterozygous on both tests.

In Part 2 of this discussion we will examine the Bsm SNP of the VDR.

In Part 3, we look at the Fok SNP.